{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T12:19:42Z","timestamp":1754396382499},"reference-count":27,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2015,6,22]],"date-time":"2015-06-22T00:00:00Z","timestamp":1434931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo, FAPESP","award":["2011-10582-1"],"award-info":[{"award-number":["2011-10582-1"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico, CNPQ"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Neuroendocrinology"],"published-print":{"date-parts":[[2015,7]]},"abstract":"<jats:p>Ketoconazole, which was initially developed as an antifungal agent, is a potent inhibitor of adrenal steroidogenesis and has therefore been used in the management of Cushing's disease. Surprisingly, the reduction of cortisol levels during ketoconazole treatment is not accompanied by the expected elevation in plasma adrenocorticotrophic hormone (<jats:styled-content style=\"fixed-case\">ACTH)<\/jats:styled-content> at the loss of negative cortisol feedback from corticotrophic cells, suggesting a direct effect of ketoconazole on these cells. To characterize the direct effects of ketoconazole, we evaluated its <jats:italic>in\u00a0vitro<\/jats:italic> effect on cell viability using the pituitary tumoural cell lines AtT\u201020 (which secretes <jats:styled-content style=\"fixed-case\">ACTH<\/jats:styled-content>), <jats:styled-content style=\"fixed-case\">GH<\/jats:styled-content>3 (which secretes <jats:styled-content style=\"fixed-case\">growth hormone<\/jats:styled-content> and prolactin) and \u03b1T3.1 (which secretes \u03b1\u2010subunit) and we also determined the expression levels of genes involved in apoptosis and <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> replication by the quantitative reverse transcription polymerase chain reaction (q<jats:styled-content style=\"fixed-case\">RT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR)<\/jats:styled-content>. We also evaluated <jats:styled-content style=\"fixed-case\">ACTH<\/jats:styled-content> levels in AtT\u201020 cells during ketoconazole treatment. We observed a ketoconazole concentration\u2010dependent decrease in pituitary cell viability and reduced <jats:styled-content style=\"fixed-case\">ACTH<\/jats:styled-content> levels in AtT\u201020 cells after removal of the drug. We also observed increased expression of cell death receptors (e.g. Fas, <jats:styled-content style=\"fixed-case\">tumour necrosis factor receptor<\/jats:styled-content>) and caspases (e.g., caspase\u20106, caspase\u20107, caspase\u20109), suggesting activation of the apoptosis pathway. In addition, we observed increased gene expression of the cell cycle inhibitors p21 and p27 in <jats:styled-content style=\"fixed-case\">GH<\/jats:styled-content>3 cells and increased expression of p21 in \u03b1T3.1 cells. In conclusion, our findings suggest that ketoconazole significantly reduces cell viability in a concentration\u2010dependent manner in pituitary tumour cell lines and is associated with an increase in apoptosis\u2010 and cell cycle regulation\u2010related gene expression.<\/jats:p>","DOI":"10.1111\/jne.12277","type":"journal-article","created":{"date-parts":[[2015,3,24]],"date-time":"2015-03-24T17:36:24Z","timestamp":1427218584000},"page":"616-623","source":"Crossref","is-referenced-by-count":6,"title":["Ketoconazole Treatment Decreases the Viability of Immortalized Pituitary Cell Lines Associated with an Increased Expression of Apoptosis\u2010Related Genes and Cell Cycle Inhibitors"],"prefix":"10.1111","volume":"27","author":[{"given":"M. F.","family":"Guzzo","sequence":"first","affiliation":[{"name":"Neuroendocrine Unit Division of Endocrinology and Metabolism Hospital das Cl\u00ednicas University of Sao Paulo Medical School S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. R.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Development Endocrinology Unit Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM 42 Hospital das Cl\u00ednicas University of Sao Paulo Medical School S\u00e3o\u00a0Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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